Are we misunderstanding beta-blockers.

In myocardial ischaemia and heart failure, beta-blockers with intrinsic sympathomimetic activity (ISA) e.g. pindolol, xamoterol, bucindolol, nebivolol, have performed poorly in reducing morbidity and mortality. In both indications beta-1 blockade is the vital active ingredient. Beta-1 blockade (bisoprolol) is now an alternative first-line choice to Ace-inhibition in the treatment of heart failure. The therapeutic role of beta-blockers in hypertension is less well understood, particularly since the new recommendations in the UK from the NICE committee stating that: 1. beta-blockers are no longer preferred as a routine initial therapy, 2. the combination with diuretics is discouraged due to the risk of induced diabetes, and 3. in younger patients first-choice initial therapy should be an ACE-inhibitor. Recent data from the Framingham Heart Study and other epidemiological studies have indicated that the development of diastolic hypertension in younger subjects is closely linked to weight-increase and an increase in peripheral resistance; such subjects have a high adrenergic drive and cardiac output. In contrast, elderly systolic hypertension mostly arises de novo via poor vascular compliance. Thus in younger, probably overweight, hypertensives (including diabetics) first-line beta-blockade has performed well in preventing myocardial infarction (a fact hidden by meta-analyses that do not take age into account). Conversely, in elderly hypertensives first-line beta-blockade (atenolol) has performed poorly in reducing cardiovascular risk (due to partial beta-2 blockade atenolol evokes metabolic disturbance and does not improve vascular compliance, or effectively lower central aortic pressure or reverse left ventricular hypertrophy). Thus beta-blockers like atenolol are ill-equipped for first-line therapy in elderly hypertension. Some beta-blockers, e.g. bisoprolol (up to 10 mg/day is highly beta-1 selective) and nebivolol (beta-2/3 intrinsic sympathomimetic activity), do improve vascular compliance and cause no metabolic disturbance. Beta-blockers as second-line to low-dose diuretics (which, by improving vascular compliance and increasing sympathetic nerve activity, create an optimal environment for beta-blockade) in elderly hypertension (including diabetics) have performed well in reducing cardiovascular events (this combination has the added bonus of reducing the risk of bone fracture by about 30%). Meta-analyses which include studies where it is unclear whether a diuretic or beta-blocker was a first-line therapy will dilute the benefit stemming from first-line diuretic/second-line beta-blockade. Hypertensives (of all ages) with ischaemia are well suited to beta-blockade.

The hydration structure of guanidinium and thiocyanate ions: implications for protein stability in aqueous solution.

Neutron diffraction experiments were carried out on aqueous solutions containing either guanidinium or thiocyanate ions. The first-order difference method of neutron diffraction and isotopic substitution was applied, and the hydration structures of two of nature's strongest denaturant ions were determined. Each ion is shown to interact weakly with water: Guanidinium has no recognizable hydration shell and is one of the most weakly hydrated cations yet characterized. Hydration of thiocyanate is characterized by a low coordination number involving around one hydrogen-bonded water molecule and approximately two water molecules weakly interacting through "hydration bonds." The weak hydration of these denaturant ions strongly supports suggestions that a major contribution to the denaturant effect is the preferential interaction of the denaturant with the protein surface. By contrast, solute species such as many sugars and related polyols that stabilize proteins are strongly hydrated and are thus preferentially retained in the bulk solvent and excluded from the protein surface.

Beta-adrenergic blocking drugs in the treatment of hypertension.

The reduction in blood pressure seen with the use of beta-blocking drugs was an unexpected finding. Initially there was resistance to their use as the reduction of cardiac output and increase in peripheral resistance from beta-blockade was considered an undesirable pharmacological action for a drug in the treatment of hypertension. However, beta-blockers have now become established in the treatment of hypertension and have been recommended as a first line choice in various guidelines, although their exact mode of action remains a matter for debate. In broad terms beta-blocking drugs are at least of similar efficacy to the other major classes of antihypertensive drugs. They may be usefully combined with other anti-hypertensives, as is often required. There is some evidence that the beta-1 selective agents are more efficacious than the non-selective beta-blockers. Notwithstanding some observations to the contrary beta-blockers are often effective antihypertensive agents in the elderly and in black patients; the combination of being elderly and black, however, appears to result in a reduced fall in blood pressure. If they are given early in pregnancy they lead to a low birth weight. Co-existant disease may influence the choice of a beta-blocker to treat hypertension. Beta-blockers are valuable agents in ischaemic heart disease, notably the control of chronic angina pectoris and to improve prognosis post-myocardial infarction. While initial dose titration has to be extremely careful, heart failure is now a strong indication for the use of a beta-blocker, as prognosis is much improved. Diabetes should no longer be regarded as a contra-indication to the use of a beta-1 selective agent. Recent work confirms that beta-blockers should be given to patients undergoing surgery who have a high cardiac risk. Outcome studies suggest overall that in younger patients beta-blockers reduce the incidence of strokes and myocardial infarction. There is no convincing evidence of a difference between the ACE inhibitor captopril and the combination of diuretic and a beta-blocker. In high risk patients, i.e. those with diabetes, no difference was seen between captopril and atenolol. Diuretics may result in better outcome measurements in the elderly compared to beta-blockade but in combination, "conventional treatment" is as effective in terms of total mortality, strokes and myocardial infarction as ACE inhibitors or calcium antagonists. Co-existant asthma remains an important contraindication to beta-blockade, but not chronic obstructive airways disease where a beta-blocker should be used with caution if it is indicated, e.g. post-infarction. Quality of life measurements, at least with beta-1 selective agents compare favourably with other anti-hypertensive drugs. Beta-blockers, without partial agonist activity, should not be stopped abruptly, particularly in patients with, or at high risk of, co-existant ischaemic disease because of the danger of post-beta-blockade cardiac sympathetic hypersensitivity; alternatively bed rest should be instituted to reduce the risk of sympathetic stimulation.

Antihypertensive treatment and the J-curve.

Unlike the brain, oxygen extraction for the heart is almost maximal at rest, so lowering coronary filling pressure (DBP) below the lower limit of autoregulation with antihypertensive drugs can lead to myocardial ischemia. This situation is exacerbated by the presence of coronary stenosis, which if more than 85% means that coronary flow reserve is virtually zero (particularly in the presence of LVH). Such patients experience a fall in coronary flow and ischemia when DBP is acutely lowered to less than the mid-80s. Ischemic episodes on the 24-hour Holter monitor in treated hypertensives are often immediately preceded by a hypotensive episode. The "J-curve" debate has been going for over 20 years. Those that deny a J-curve relationship between treated DBP and myocardial infarction (MI) quote the continuous DBP/MI relationship seen in the large cohort of MRFIT screenees (with ischemic patients weeded out). However, the actual MRFIT (and similar HDFP) study patients with abnormal ECGs (ischemia or LVH), in contrast to those with normal ECGs, in the special-care group experienced an excess of coronary events associated with a DBP 5 mmHg lower than the referred-care group. Other studies, including the prospective HOT study, have indicated that ischemic hypertensives gain optimal results when DBP is lowered to the mid- to low 80s; below this level, the frequency of MI increases. This treatment-induced J-curve should not be confused with Nature's untreated J-curve, which results from the association of a low DBP (wide pulse-pressure) due to aging, noncompliant arteries, and an increasing frequency of ischemic events. A reasonable conclusion from most treatment studies (including HOT) is that in nonischemic hypertensives there is little point in lowering DBP below the mid- to low 80s in terms of MI prevention--though it is safe to do so. In contrast, ischemic hypertensives should not have their DBP lowered to less than the mid- to low 80s for fear of increasing the risk of MI.

New approaches to the uses of beta blocking drugs in hypertension.

After a slow start, beta-blockers have become widely used as first-line agents in the treatment of hypertension, and recommended as such in recently published guidelines. There is evidence that the beta1-selective agents are more efficacious than non-selective blockers that inhibit both beta1 and beta2 receptors. Notwithstanding some earlier evidence to the contrary, it appears that beta1-selective drugs are equi-effective in young and elderly whites, younger, ie, under mid 60s, blacks. It is with the combination of age and being black that beta-blockers are usually less useful than some other groups of antihypertensive drugs, most notably calcium antagonists and diuretics. Primary prevention studies indicate beta-blockers reduce the incidence of cerebro-vascular disease and coronary heart disease in younger patients but they appear less effective than diuretics in the elderly. Beta-blockers are particularly indicated in patients who have experienced a myocardial infarction where they are often under used. There is some evidence that even in post-infarction patients with co-existent chronic obstructive airways disease, usually regarded as a contra-indication, experience an improved 2-year survival with the use of beta-blockers. Recently they have also been demonstrated to improve prognosis in heart failure patients, previously regarded as a contra-indication. Likewise, recent studies have shown that atenolol was at least as effective as captopril in improving the outlook in hypertensive patients with non-insulin dependent diabetes. While earlier comparisons with the non-selective lipid soluble propranolol indicated otherwise, comparisons with beta1-selective agents have indicated a similar effect on quality of life assessments with angiotensin-converting enzyme inhibitors.

The beta 1 hyperselectivity in beta-blocker treatment.

Coronary heart disease (CHD) is the most common cause of death in Western industrialized countries. CHD is more common in individuals with clustering of coronary risk factors, e.g., hypertension and blood lipid abnormalities. There is a good rationale for the use of beta-blockers for prevention of myocardial infarction (MI) in high-risk groups, as beta-blockade decreases myocardial oxygen consumption and, by decreasing turbulent blood flow patterns, reduces endothelial shear forces, thus making plaque rupture (and the ensuing thrombotic events) less likely. Clinical trial data have shown beta-blockade to be effective in the prevention of cardiovascular end points. In both younger and older hypertensive patients there is a significant reduction in the incidence of stroke and in younger hypertensive patients there is about a 15% reduction in MI. Left ventricular hypertrophy (particularly by ECG) is significantly diminished. In secondary prevention of MI there is about 15% reduction after early and 25-30% reduction after late intervention with beta-blockers given post-MI. In both stable and unstable angina, beta-blockade appears to be beneficial not only in improvement of symptoms but also in prevention of hard cardiovascular end points. There are also promising data suggesting that beta-blockade is useful in endothelial protection and atheroma prevention, and benefits patients with hypertrophic cardiomyopathy and heart failure. beta-Blockers have evolved from early nonselective agents, e.g., propranolol, to modern highly beta 1-selective agents, e.g., bisoprolol. beta 1-Blockade is the essential element that leads to the above cardiovascular benefits in addition to improving the quality of life (similar to angiotensin-converting enzyme inhibitors).

J curve in antihypertensive therapy--does it exist? A personal point of view.

Coronary flow is maintained in the face of changing perfusion pressure (approximates to diastolic blood pressure [DBP]) by the process of autoregulation. A normal coronary artery is able to dilate fivefold (coronary flow reserve of 5); by contrast, coronary flow reserve falls in the presence of left ventricular hypertrophy [LVH] and/or coronary artery disease. Thus a fall in DBP that is normally well tolerated causes a fall in coronary flow, ECG changes, and left ventricular dysfunction in the presence of LVH and coronary artery disease. Such high-risk patients exhibit a J-curve relationship between DBP and death from coronary artery disease; lowering DBP (phase 5) to below the mid 80s would be imprudent in such patients.

Accuracy of the Omron HEM 706 portable monitor for home measurement of blood pressure.

A reliable, well-validated home blood pressure (BP) self-measurement device could have an important role in the management of hypertension by the early identification of 'white coat' hypertensives. Under rigorous assessment such devices have not performed well in the estimation of DBP, particularly in the hypertensive range. We assessed the Omron HEM 706 device (oscillometric) for home measurement of BP according to the standards set out by the British Hypertension Society protocol and the Association for the Advancement of Medical Instrumentation (AAMI). The device was compared with simultaneous measurements made by two 'blinded' observers using a standard mercury sphygmomanometer in the same arm in 85 subjects aged 17-76 years with a wide range of BPs. The device was satisfactory over the whole BP range (SBP 89-188 mmHg, DBP 44-118 mmHg), with a B grading for SBP and a C grading for DBP (British Hypertension Society protocol) and a PASS for both SBP and DBP (AAMI). For the diastolic hypertensive range 90-120 mmHg, where most clinical decisions are made, the device scored a B grade for SBP and an A grade for DBP, with a PASS for both SBP and DBP. We conclude the Omron HEM 706 device for home BP measurement is highly satisfactory, particularly in the mild to moderate hypertension range, and is suitable for clinical use.

Phosphodiesterase III inhibitors: long-term risks and short-term benefits.

Heart failure is now viewed as a disorder of the circulation, not merely the heart, which becomes manifest only when certain compensatory mechanisms break down. After treatment with diuretics, the two main strategies in treating heart failure involve decreasing the work of the heart by vasodilatation or increasing ventricular contractility by positive inotropic agents. It is now apparent, however, that the resulting hemodynamic benefit need not equate with long-term clinical improvement or increased longevity; indeed, the reverse can be true. Inhibitors of phosphodiesterase III, which is specific for the breakdown of cyclic adenosine monophosphate (cAMP), produce useful hemodynamic effects following intravenous and oral dosing, but have not fulfilled their initial promise in the chronic oral treatment of heart failure patients. The reason for reduced survival in the long-term studies of milrinone is not clear, but cardiac arrhythmias, possibly resulting from the increased intracellular levels of cAMP, may be responsible. However, intravenous usage may not suffer from the same limitations as chronic oral dosing. Short-term intravenous administration produces the expected beneficial hemodynamic effects of positive inotropism and vasodilatation. Though infusions of milrinone have been shown to enhance atrioventricular conduction in some, but not all, studies, there appears to be no significant increase in ventricular premature contractions, or ventricular or sustained tachyarrhythmias. Because milrinone does not have a significant adverse effect on His-Purkinje conduction, its use should be well tolerated in patients with intraventricular conduction disturbances. However, accurate assessment of the mortality risk and benefit of short-term intravenous treatment remains to be made in sufficiently powerful prospective, randomized controlled studies.(ABSTRACT TRUNCATED AT 250 WORDS)

The xamoterol experience in the treatment of heart failure.

Beta blockers may benefit patients with dilated cardiomyopathy but low output failure can be a problem. Thus a beta 1-selective beta blocker with about 45% intrinsic sympathomimetic activity (ISA), such as xamoterol, was thought to have a desirable pharmacologic profile. Long-term studies of xamoterol in patients with idiopathic dilated cardiomyopathy have shown improved cardiac performance and exercise tolerance, while exercise heart rate, left ventricular ejection fraction, and pulmonary artery wedge pressure were decreased. This improvement in exercise capacity and overall quality of life in patients treated with xamoterol has been confirmed in further controlled trials of patients with mild-to-moderate heart failure (NYHA class I and II). However, in patients with moderate-to-severe heart failure (NYHA class III and IV), mortality was unfavorably influenced by xamoterol. The therapeutic role of xamoterol in patients with heart disease needs further refinement.

The role of coronary perfusion pressure.

Coronary flow is normally autoregulated so that within wide limits of changes in perfusion pressure (which approximate to diastolic BP) blood flow to the heart remains constant. Thus, as perfusion pressure falls, the coronary arterioles dilate to maintain flow; under basal conditions a five-fold increase in coronary flow can occur, i.e. a flow reserve of five. Coronary flow reserve is markedly impaired in the presence of severe coronary artery stenosis and/or LVH. In the presence of severe stenosis and LVH a fall in perfusion pressure (DBP), which would be normally well tolerated, results in a fall of coronary flow, ECG changes and ventricular dysfunction (fall in ejection fraction instead of the usual increase). The above mechanisms underlie the J-curve relationship between DBP and myocardial infarction (MI) in high risk hypertensives. In the absence of overt coronary artery disease (CAD) and LVH, the lower the DBP the better. However in the presence of CAD and LVH lowering the DBP (phase 5) to below the low-mid 80s results in an increased frequency of MI.